白血病
癌症研究
抗体
免疫学
细胞毒性T细胞
生物
单克隆抗体
体外
生物化学
作者
Padma Akkapeddi,Rita Fragoso,Julie A. Hixon,Sofia Ramalho,Mariana L. Oliveira,Tânia Carvalho,Andreas Gloger,Mattia Matasci,Francisco Corzana,Scott K. Durum,Dario Neri,Gonçalo J. L. Bernardes,Jorge M. M. Barata
出处
期刊:Leukemia
[Springer Nature]
日期:2019-03-08
卷期号:33 (9): 2155-2168
被引量:41
标识
DOI:10.1038/s41375-019-0434-8
摘要
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12–MMAE antibody–drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role.
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